Aminoalkoxy-or aminomethyl-triarylalkenones

ABSTRACT

NOVEL COMPOUNDS OF THE FORMULA: ((R2,R5-PHENYL)(R3-PHENYL)-C=C(-CO-R1)-),R4-BENZENE     WHEREIN R1 IS LOWER ALKYL; EACH OF R2, R3, AND R4 IS HYDROGEN, LOWER ALKYL, HALOGEN, HYDROXY, LOWER ALKOXY, DILOWERALKYLAMINOLOWERALKOXY OR TRIFLUOROMETHYL; AND R5 IS HYDROGEN, LOWER ALKYL, OR DILOWERALKYLAMINOMETHYL, PROVIDED THAT WHEN R5 OR DILOWERALKYLAMINOMETHYL R2 IS HYDROXY IN THE PARA-POSITION OF SAID BENZENE RING AND THE DILOWERALKYLAMINOMETHYL IS ORTHO TO SAID HYDROXY GROUP; AND PAHRMACOLOGICALLY ACCEPTABLE, NON-TOXIC ACID ADDITION SALTS OF THE BASIC COMPOUNDS. THESE COMPOUNDS POSSESS ESTROGENIC, ANTI-ESTROGENIC AND ANTI-INFLAMMATORY ACTIVITES.

United States Patent 3,721,712 AMINOALKOXY- 0R AMINOMETHYL-TRIARYLALKENONES Frank P. Palopoli and Harvey D. Benson, Cincinnati,

Ohio, assignors to Richardson-Merrell Inc., New York,

No Drawing. Original application Aug. 19, 1968, Ser. No.

753,741, now Patent No. 3,634,517. Divided and this application Mar. 25,1971, Ser. No. 128,200

Int. Cl. C07c 93/06 US. Cl. 260570 R 6 Claims ABSTRACT OF THE DISCLOSURENovel compounds of the formula:

This application is a divisional application of application Ser. No.753,741, filed Aug. 19, 1968 and now US. Pat. No. 3,634,517.

This invention relates to novel physiologically active triarylalkenonesand to a process for their manufacture.

The novel triarylalkenones of this invention can be represented by theformula:

wherein R is lower alkyl; each of R R and R is hydrogen, lower alkyl,halogen, hydroxy, lower alkoxy, diloweralkylaminoloweralkoxy ortrifluoromethyl; and R is hydrogen, lower alkyl, ordiloweralkylaminomethyl, provided that when R is diloweralkylaminomethylR is hydroxy in the para-position of said benzene ring and thediloweralkylaminomethyl is ortho to said hydroxy group.

Many of the compounds of this invention are unsym-,

metrical ethylenes and as such are capable of existing as cis or transgeometric isomers. It should be understood that this invention relatesto the separate geometric isomers as well as to mixtures of suchisomers.

The term lower as used herein to describe alkyl relates to such a grouphaving from 1 to 4 carbon atoms and preferably 1 to 2 carbon atoms.Illustrative of lower alkyl there can be mentioned: methyl, ethyl,propyl, isopropyl and butyl. Illustrative of lower alkoxy there can bementioned: methoxy, ethoxy and butoxy. Illustrative ofdiloweralkylaminomethyl there can be mentionel: di-

ice

methylaminomethyl, diethylaminomethyl, and dibutylaminomethyl.Illustrative of diloweralkylaminoalkoxy there can be mentioned:diethylaminoethoxy; dimethylaminopropoxy; and the like. Illustrative ofhalogens there can be mentioned chlorine, bromine and fluorine, butpreferably chlorine.

Salts of the novel basic compounds, i.e., compounds having an aminogroup, of this invention are particularly pharmacologically acceptable,non-toxic acid addition salts, such as those with inorganic acids, e.g.,hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like, withorganic carboxylic acids, e.g., acetic, propionic, glycolic, lactic,pyruvic, oxalic, malonic, succinic, fumaric, malic, tartaric, citric,ascorbic, maleic, hydroxymaleic, dihydroxymaleic, fumaric, benzoic,phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic,mandelic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2acetoxybenzoic acid and the like, or organic sulfonic acids, e.g.,methane sulfonic, ethane sulfonic, Z-hydroxyethane sulfonic, p-toluenesulfonic acid and the like. Neutral or acid salts may be formed.

The novel compounds of this invention (including acidaddition saltsthereof) have anti-inflammatory activity and endocrine activity such asestrogenic and anti-estrogenic activity. Estrogenic activity wasdemonstrated by an increase in the uterus weight of female animals,e.g., mammals such as mice, after administration of a novel compound ofthis invention when such animals were compared with untreated controls.The anti-estrogenic activity was evidenced by a greater uterine weightin mammals such as mice or rats treated with a conventional estrogen ascompared to similar animals treated with such estrogen and a novelcompound of this invention. Antiinfla-rnmatory action was demonstratedby one or more of the following tests in mammals such as mice or rats byinhibition of inflammatory edema formation, inhibition of granulomaformation in the anti-fibrosis test, or inhibition of the PMNinfiltration in the PMN infiltration test.

The novel compounds of this invention can be used as medicaments in theform of pharmaceutical preparations which contain the novel compounds inadmixture with a pharmaceutical organic or inorganic solid or liquidcarrier suitable for enteral, e.g., oral, or parenteral, e.g.,subcutaneous, administration. The pharmaceutical preparations can be insolid form, e.g., tablets or capsules or in liquid form, for example, insolutions, suspensions or emulsions. The quantity of novel compoundmedicament in the unit dosage can vary over a wide range, for example,from about 30 to 300 mg., depending on the mode of administration andthe animal being treated. The quantity of drug administered per dosagecan vary over a wide range such as that of from less than about 0.3 toover 250 mg. per kg. of animal weight, in the case of estrogenic oranti-estrogenic use. Preferably, the dosage will range from about 1 to20 mg. per kg. of animal weight for the estrogenic or anti-estrogenicuse. In the case of anti-inflammatory use the dosages can vary from lessthan about 0.3 to 300 mg. per kg. of animal weight and preferably fromabout 1 to 20 mg. per kg. of animal weight. Illustratively, estrogenicand anti-estrogenic activities can be obtained after subcutaneousinjection in mice of one dose ranging from 0.03 to 300 mg. per kg. ofanimal Weight when administered to female mice. Anti-inflammatoryactivity can be evidenced after oral administration of 3 to milligrams'(-mg.) per kilogram (kg) of animal weight, as little as 0.3 mg. per kg.of animal weight subcutaneously, and 3 to 30 mg. per kg. when appliedtopically. As antiinfiammatory agents, the compounds can be useful inalleviating symptoms of collagen diseases and in the topical treatmentof inflammation.

The novel compounds of this invention can be prepared by a number ofroutes. Illustratively, they can be prepared 3 by reacting anorganometallic reagent, such as lower alkyllithium, e.g., methyllithium,with a triaryl acrylonitrile and subsequently hydrolyzing the iminewhich is formed by the use of an aqueous acid medium. This genericreaction can be illustrated as follows:

wherein each of R R R R and R have the same meanings given hereinbefore.The imine intermediate can be isolated prior to hydrolysis or it may beconverted to the triarylalkenone without prior isolation. When asubstituent on the aryl groups is hydroxy, the pyranoxy blocking groupcan be formed by conventional techniques in order to block the hydroxylin the reaction. In the hydrolysis of the imine, the pyranoxy group isconverted back to the hydroxy.

The diloweralkylaminoloweralkoxy derivatives of the triarylalkenones ofthis invention can also be prepared by reacting the appropriatehydroxy-substituted triarylalkenone with a diloweralkylaminoloweralkylhalide in an alkaline medium as shown by the following formulae:

4 wherein each of R R R and R have the meaning given hereinabove.

Also, by reacting the appropriate hydroxy-substituted triarylalkenonewith formaldehyde and a secondary amine in refluxing ethanol, adiloweralkylaminornethyl group can be inserted ortho to the hydroxygroup as shown in the following formulae:

| (CHmNCHz The triarylacrylonitrile reactants are for the most partknown compounds. Those not specifically disclosed in the literature canbe prepared by conventional techniques disclosed for the known compoundssuch as the following techniques:

(a) Base catalyzed condensation of a phenylacetonitrile and abenzophenone;

(b) Reaction of a triarylhaloethylene with cuprous cyanide; or

(c) Formulation of a phenolic hydroxy group on an existingtriarylacrylonitrile by cleavage of the corresponding methoxy derivativewith pyridine hydrochloride. The following examples are illustrative ofthe invention.

EXAMPLE 1 Preparation of 3,4-diphenyl-4-(p-methoxyphenyl)-3- buten-Z-oneMethyl lithium, prepared from 14.1 g. (0.1 mole) of methyl iodide and1.75 g. of lithium wire in ether was added to 10 g. (0.033 mole) of2,3-diphenyl-3-(p-methoxyphenyl)acrylonitrile suspended in ether. Thereaction was stirred until the nitrile had dissolved and then it wasrefluxed for one hour. The reaction was poured onto ice and the etherlayer collected. The imine intermediate was extracted from the etherwith 10% hydrochloric acid. The acid layer was then made basic with 10%NaOH and the free base of the imino compound taken up in ether. Thehydrochloride salt of the imino compound was prepared by the addition ofethereal hydrochloric acid. The ether was decanted and the residuedissolved in water and heated on the steam bath for two hours tohydrolyze the imino compound. The oil Which separated was dissolved inmethylene chloride and dried, and the solvent was then removed byevaporation on a steam bath. The residue was chromatographed on a columnof alumina using methylene chloride for elution. The product wascrystallized from ethanol and petroleum ether (B.P. 60 C.)

NaO CH CzHsOH QED yielding a mixture of cis-trans isomers of3,4-diphenyl-4- (p-methoxyphenyl)-3-buten-2one which melted at 100- 108C. This compound exhibits estrogenic, anti-estrogenic, andanti-inflammatory activities.

EXAMPLE 2 Prepararation of 3,4-dipheny1-4-(p-hydroxyphenyl) -3-buten-Z-one Methyl lithium prepared from 14.1 g. (0.1 mole) of methyliodide and 2 g. of lithium wire was added to g. (0.034 mole) of 2,3diphenyl-3-(p-hydroxyphenyl)acrylonitrile suspended in ether.Tetrahydrofuran (400 ml.) was added and the solution was refluxed for 2hours. The reaction was then poured onto ice and the water layer wascollected. The water layer was made acidic with 10% hydrochloric acidand heated on the steam bath for three hours to hydrolyze the iminointermediate. The product separated as a solid. Recrystallization firstfrom ethanol and water and then from benzene and petroleum ether (B.P.4060 C.) gave 3,4-diphenyl-4-(p-hydroxyphenyl)- 3-buten-2-one whichmelted at 203207 C. This compound exhibits estrogenic andanti-esterogenic activities.

EXAMPLE 3 Preparation of 3,4-diphenyl-4-(p-tolyl)-3-buten-2-one When the2,3,3-triphenylacrylonitrile in the following Example 4 was replacedwith 2,3-diphenyl-3-(p-tolyl)acry lonitrile there was obtained a mixtureof the cis-trans isomers of 3,4-diphenyl-4-(p-tolyl)-3-buten-2-one whichmelted at 112-120 C. This compound exhibits estrogenic andanti-estrogenic activities.

EXAMPLE 4 Preparation of 3,4,4-triphenyl-3-buten-2-one Methyl lithium,prepared from 14.1 g. (0.1 mole) of methyl iodide and 1.5 g. of lithiumwire in ether, was added to 10 g. (0.036 mole) of2,3,3-tripl1enylacrylonitrile suspended in ether. The reaction wasrefluxed for three hours, cooled and poured onto ice. The ether layerwas collected and the imine intermediate was extracted from the etherwith 10% hydrochloric acid. Heating the acid extract on the steam bathwith stirring for three hours resulted in the hydrolysis of the iminocompound, and the separation of the product as a solid, which wascollected by filtration. This material was dissolved in methylenechloride, dried over magnesium sulfate, treated with charcoal andfiltered. The solvent was then removed by evaporation on the steam bath.The solid residue was recrystallized first from petroleum ether (B.P.75-90 C.) and then form ethanol to give the desired 3,4,4-triphenyl-3-buten-Z-one as a white crystalline solid which melted at 149-152 C. Thiscompound exhibits estrogenic and antiestrogenic activities.

EXAMPLE 5 Preparation of 4-(p-ch1orophenyl)-3,4-diphenyl-3-buten- 2-oneWhen the 2,3,3-triphenylacrylonitrile in Example 4 was replaced with 3(p-chlorophenyl) 2,3-diphenylacrylonitrile there was obtained a mixtureof the cis-trans isomers of 4(p-chlorophenyl)-3,4-diphenyl-3-buten-2-one which melted at 110123 C.This compound exhibits estrogenic and anti-inflammatory activities.

EXAMPLE 6 Preparation of 4- (m-chlorophenyl -3 ,4-diphenyl-3 -buten-2-one When the 2,3,3-triphenylacrylonitrile in Example 4 was replacedwith 3 (m-chlorophenyl) 2,3-diphenylacrylonitrile there was obtained amixture of the cis-trans isomers of4-(m-chlorophenyl)-3,4-diphenyl-3-buten-2-one which melted at 105 138 C.Recrystallization of 4-(m-chlorophenyl) 3,4 diphenyl-3-buten-2-one fromcyclohexane yielded the higher melting isomer of 4-(m-chlorophenylEXAMPLE 7 Preparation of 4,4-bis(m-chlorophenyl)-3-phenyl-3- buten-2-oneWhen the 2,3,3-triphenylacrylonitrile in Example 4 was replaced with 3,3bis(m-chlorophenyl)-2-phenylacrylonitrile, there was obtained 4,4bis(m-chlorophenyl)-3- phenyl-3-buten-2-one which melted at 124-427 C.This compound exhibits anti-estrogenic activity.

EXAMPLE 8 Preparation of 3,4-diphenyl-4- [p-(B-diethylaminoethoxy)'phenyl]-3-buten-2-one A solution of 5 g. (0.016 mole) of3,4-diphenyl-4-(phydroxyphenyl)-3-buten-2-one, 0.85 g. (0.016 mole) ofsodium methoxide, and 2.15 g. (0.016 mole) of fl-diethylaminoethylchloride in ml. of ethanol were allowed to stand at room temperature for55 hours. The solvent was removed on the steam bath under reducedpressure, and the residue dissolved in ether and extracted with water.The ether layer was dried and filtered. Alcoholic hydrochloric acid wasadded and the oil which separated was crystallized from ethyl acetateyielding 3,4-diphenyl 4-[p-(fl-diethylaminoethoxy)-phenyl]-3-buten-2-one hydrochloride which melted at 188190 C. This compound exhibitsestrogenic, anti-estrogenic, and anti-inflammatory activities.

EXAMPLE 9 Preparation of 4-[4-hydroxy-3-(dimethylaminomethyl) phenyl]-3,4-diphenyl-3-buten-2-one A solution of 5 g. (0.016 mole) of3,4-diphenyl-4-(phydroxyphenyl)-3-buten-2-one, 5.89 g. (0.033 mole) of a25% aqueous dimethylamine solution and 2.6 g. (0.032 mole) of formalin(37%) in 75 ml. of ethanol was refluxed for two hours. The solvent wasremoved under reduced pressure and the residue was dissolved in ether,and treated with a minimum amount of ethereal hydrochloric acid. Theresulting solid was recrystallized from a methanol-butanone mixtureyielding the hydrochloride salt of 4[4-hydroxy-3-(dimethylaminomethyl)phenyl]-3,4- diphenyl-3-buten-2-onewhich melted at 20921l C. This compound exhibits anti-estrogenicactivity.

EXAMPLE 10 Preparation of 3,4-diphenyl-4- (m-tolyl)-3-buten-2-one Whenthe 2,3,3-triphenylacrylonitrile in Example 4 was replaced with 2,3diphenyl-3-(m-tolyl)acrylonitrile, a mixture of the cis-trans isomers of3,4 diphenyl-4-(mtolyl)-3-buten-2-one was obtained which melted at 108--138 C.

Recrystallization of 3,4 diphenyl-4-(m-t olyl)-3-buten- 2-one from ethylacetate gave the higher melting isomer of3,4-diphenyl-4-(m-tolyl)-3-buten-2-one which melted at 136143 C. Thelower melting isomer was obtained from the mother liquor by removing thesolvent and recrystallizing the residue from ether to yield the productwhich melted at 117-124 C. The subject compound exhibits anti-estrogenicactivity.

EXAMPLE 11 Preparation of 3,4-diphenyl-4-(m-methoxyphenyl)-3-buten-Z-one When the 2,3,3-triphenylacrylonitrile in Example 4 wasreplaced with 2,3-diphenyl-3- (m-methoxyphenyl) acrylonitrile, there wasobtained 3,4-diphenyl-4-(m-methoxyphenyl)-3-buten-2-one which melted at116 149" C. as a mixture of cis-trans isomers. This compound exhibitsestrogenic and anti-estrogenic activities.

EXAMPLE 12 3,4-diphenyl-4- m-trifluoromethylphenyl) -3-buten-2-one Whenthe 2,3,B-triphenylacrylonitrile in Example 4 was replaced with2,3-diphenyl-3-(m-trifiuoromethylphenyl)- acrylonitrile, there wasobtained 3,4-diphenyl-4-m-trifiuoromethylphenyl) 3-buten-2-one whichmelted at 105- 109 C. This compound exhibits anti-estrogenic activity.

EXAMPLE 13 Preparation of 3,4-diphenyl-4-(m-hydroxyphenyl)-3-buten-2-one When the 2,3 diphenyl-3-(p-hydroxyphenyl)acrylonitrile inExample 2 was replaced with2,3-diphenyl-3-(mhydroxyphenyl)aerylonitrile, using ether as the onlysolvent, there was obtained3,4-diphenyl-4-(m-hydroxyphenyl)-3-buten-2-one which melted at 175l77 C.This compound exhibits estrogenic, anti-estrogenic, andanti-inflammatory activities.

EXAMPLE 14 Preparation of 3,4-diphenyl-4- [m- (li-diethylaminoethoxy)phenyl] -3-buten-2-one A mixture of 3.75 g. (0.012 mole) of3,4-diphenyl- 4-(m-hydroxyphenyl)-3-buten-2-one, 0.48 g. (0.012 mole) ofsodium hydroxide and 1.63 g. (0.012 mole) of [ii-diethylaminoethylchloride in water was treated with ethanol to effect solution. Thissolution was stirred at room temperature for 24 hours, warmed on thesteam bath for 30 minutes and then cooled. The solid which separated wascollected and recrystallized from petroleum ether (B.P. 4060 C.)yielding 3,4-diphenyl-4-[m-(B-diethylamirwethoxy)phenyl]-3-buter1-2-one,which melted at 71-73 C. This compound exhibits estrogenic,anti-estrogenic, and inflammatory activities.

EXAMPLE 15 Preparation of 4,4-diphenyl-3-(m-methoxyphenyl)-3-'buten-2-one When the 2,3,3-triphenylacrylonitrile in Example 4 wasreplaced with 3,3-diphenyl-2-(m-methoxyphenyl) acrylonitrile, there wasobtained 4,4-diphenyl-3-(m-methoxyphenyl)-3-buten-2-one which melted at102l05 C. This compound exhibits estrogenic and anti-estrogenicactivities.

EXAMPLE 16 Preparation of 4,4-diphenyl-3-(m-hydroxyphenyl)-3-buten-Z-one When the 2,3-diphenyl-3 (p hydroxyphenyl)acrylonitrile inExample 2 was replaced with 3,3-diphenyl-(mhydroxyphenyl)acrylonitrile,using ether as the only solvent, there was obtained4,4-diphenyl-3-(m-hydroxyphenyl)-3-buten-2-one which melted at 139-141C. This compound exhibits estrogenic and anti-estrogenic activities.

EXAMPLE 17 Preparation of 4,4-diphenyl-3-[m- (B-diethylaminoethoxy)phenyl]-3-buten-2-one A solution of 6.5 g. (0.02 mole) of4,4-diphenyl-3-(mhydroxyphenyl)-3-buten-2-one and 0.9 g. (0.022 mole) ofsodium hydroxide was made in water and alcohol, and 3 g. (0.022 mole) ofB-diethylaminoethyl chloride was added. The reaction was refluxed for 1hour and allowed to stand for 64 hours. Water was added and thesemi-solid which separated was collected and dissolved in methylenechloride and dried over magnesium sulfate and solvent was removed byevaporation on a steam bath. The residue was converted to the citratesalt yielding 4,4-diphenyl-3- [m-( ;9-diethylaminoethox'y)phenyl]-3-buten-2-one dihydrogen citrate whichmelted at 98103 C. with decomposition. This compound exhibits estrogenicand antiestrogenic activities.

EXAMPLE 18 Preparation of 3,4-diphenyl-4-(m-fluorophenyl)-3-buten-EXAMPLE 19 Preparation of 3-(m-chlorophenyl)-4,4-diphenyl-3-buten- 2-oneWhen the 2,3,S-triphenylacrylonitrile in Example 4 was replaced with2-(m-chlorophenyl)-3,3-diphenylacrylonitrile, there was obtained3-(m-chlorophenyl)-4,4- diphenyl-3-buten-2-one which melted at 135138 C.This compound exhibits estrogenic and anti-estrogenic activities.

EXAMPLE 20 Preparation of 3-(p-chloropheny1)-4,4-diphenyl-3-buten- 2-oneWhen the 2,3,3-triphenylacrylonitrile in Example 4 was replaced with2-(p-chlorophenyl)-3,3 diphenylacrylonitrile, there was obtained3-(pchlorophenyl)-4,4-diphenyl-3-buten-2-one which melted at 104-105" C.This compound exhibits estrogenic and anti-estrogenic activities.

EXAMPLE 21 Preparation of 3-(o-chlorophenyl)-4,4-diphenyl-3-buten 2-0neWhen the 2,3,3-triphenylacrylonitrile in Example 4 was replaced with2-(o-chlorophenyl)-3,3-diphenylacrylonitrile, there was obtained3-(o-chlorophenyl)-4,4-di phenyl-3-buten-2-one which melted at l50152 C.This compound exhibits estrogenic and anti-estrogenic activities.

EXAMPLE 22 Preparation of 4,4-diphenyl-3- (m-fiuorophenyl)-3-buten-2-one When the 2,3,3-triphenylacrylonitrile in Example 4 was replacedwith 3,3-diphenyl-2-(m fiuorophenyl)acrylonitrile, there was obtained4,4-diphenyl-3-(m-fiuorophenyl)-3-'buten-2-one which melted at 127 C.This compound exhibits estrogenic and anti-estrogenic activities.

EXAMPLE 23 Preparation of 4-(3,4-dimethylphenyl)-3,4-diphenyl-3-buten-Z-one When the 2,3,3-triphenylacrylonitrile in Example 4 wasreplaced with 3-(3,4-dimethylphenyl)-3,4-diphenyl acrylonitrile, therewas obtained a mixture of cis-trans isomers which melted at l43 C.Recrystallization from petroleum ether (7590 C.)-benzene yielded thephenyl-3-buten-2-one which melted at 142144 C. The residue from themother liquor was crystallized from petroleum ether (7590 C.) to givethe low melting isomer of 4-(3,4-dimethylphenyl)-3,4-diphenyl-3-buten 2-one which melted at 133.0135.5 C. The subject compound exhibitsestrogenic activity.

9 EXAMPLE 24 Preparation of 1,1,2-triphenyl-1-hepten-3-one When themethyl lithium in Example 4 was replaced with n-butyl lithium, there wasobtained 1,1,2-triphenyl-1- hepten-B-one which melted at 115-116 C. Thiscompound exhibits estrogenic and anti-estrogenic activities.

EXAMPLE 25 Preparation of 3,4,4-tris(p-methoxyphenyl)-3-buten-2-one Whenthe 2,3,3-triphenylacrylonitrile in Example 4 was replaced with2,3,3-tris(p-methoxyphenyl)acrylonitrile there was obtained3,4,4-tris(p-methoxyphenyl)-3-buten- 3-one which melted at 116.0-1 17.5C. This compound exhibits estrogenic activity.

EXAMPLE 26 Preparation of 4,4-bis (p-methoxyphenyl) -3-(o-chlorophenyl)-3-buten-2-one When the 2,3,3-triphenylacrylonitrile in Example 4 wasreplaced with 3,3-bis(p-methoxyphenyl)-2-(o chlorophenyl)acrylonitrilethere was obtained 4,4-bis(p-methoxyphenyl)-3-(o-chlorophenyl)-3-buten 2one which melted at 134-136 C. This compound exhibits estrogenic,anti-estrogenic, and anti-inflammatory activities.

EXAMPLE 27 Preparation of 4,4-bis(p-hydroxyphenyl)-3-(o-chlorophenyl-3-huten-2-one When the 2,3,3-triphenylacrylonitrile in Example 4 wasreplaced with 3,3-bis(p-pyranoxypheny1) 2 (o-chlorophenyl )acrylonitrilethere was obtained 4,4-bis(p-hydroxyphenyl)-3-(o-chlorophenyl)3-buten-2one which melted at 235237 'C. This compound exhibits estrogenic andanti-estrogenic activities.

EXAMPLE 28 'Preparation of 4,4-bis[p-(B-diethylaminoethoxy)phenyl]- 3(o-chlorophenyl) -3 buten-Z-one A solution of 15 g. (0.041 mole) of4,4-bis(p-hydroxyphenyl)-3-(o-chlorophenyl)-3-buten-2 one and 4.86 g.(0.09 mole) of sodium methoxide in ethanol was refluxed for minutes. A12.2 g. (0.09 mole) quantity of lit-diethylaminoethyl chloride was addedand refluxing was continued for 3 hours. The solvent was removed underreduced pressure, and the residue was dissolved in ether and extractedwith aqueous sodium hydroxide. The ether layer was dried and filtered.The solvent was removed on the steam bath. The residue was converted tothe his citrate salt yielding 4,4-bis[p-(fi-diethylaminoethoxy)phenyl]-3-(o-chlorophenyl)-3-buten-2-one bis dihydrogen citratemonohydrate which decomposed at 95-98 C. This compound exhibitsestrogenic and anti-estrogenic activities.

EXAMPLE 29 Preparation of 4-(p-hydroxyphenyl)-3-(p-methoxypheny1)-4-phenyl-3 -buten-2-one When the 2,3-diphenyl-3-(phydroxyphenyl)acrylonitrile in Example 2 was replaced with3-(p-hydroxyphenyl)-2-(p-methoxyphenyl)-3-phenylacrylonitrile there wasobtained a mixture of the cis and trans isomers of 4-(p-hydroxyphenyl)-3-(p-methoxyphenyl) 4 phenyl 3- buteu-2-one whichmelted at 185-190 C. This compound exhibits estrogenic andanti-estrogenic activities.

1 0 EXAMPLE 30 Preparation of 4-[p-(B-diethylaminoethoxy)-phenyl]-3-(p-methoxyphenyl-4-phenyl-3-buten-2-one A solution of 9 g. (0.029 mole)of 4-(p-hydroxyphenyl)-3-(p-methoxyphenyl)-4-phenyl-3-buten 2 one and1.62 g. (0.03 mole) of sodium methoxide in ethanol was refluxed for 5minutes. A 4.05 g. (0.03 mole) quantity of fi-diethylaminoethyl chloridewas added and rewherein R is lower alkyl; each of R R and R is hydrogen,lower alkyl, halogen, hydroxy, lower alkoxy,diloweralkylaminoloweralkoxy or trifiuoromethyl; and R is hydrogen,lower alkyl, or diloweralkylaminomethyl, with the proviso that at leastone of R R or R is diloweralkylaminoloweralkoxy when R is eitherhydrogen or lower alkyl, and further provided that when R isdiloweralkylaminomethyl, R hydroxy in the para-position of said benenering and the diloweralkylaminomethyl is ortho to said hydroxy group; ora pharmaceutically acceptable acid addition salt of the compoundthereof.

2. A compound of claim 1 wherein R is diethylaminoethoxy in thepara-position, each of R R and R is hydrogen, and R is methyl.

3. A compound of claim 1 wherein R is diethylaminoethoxy in themeta-position, each of R R and R is hydrogen, and R is methyl.

4. A compound of claim 1 wherein each of R R and R is hydrogen, R isdiethylaminoethoxy in the metaposition, and R is methyl.

5. A compound of claim 1 wherein each of R and R is diethylaminoethoxyin the para-position, R is hydrogen, R is chlorine in theortho-position, and R is methyl.

6. A compound of claim' 1 wherein R is hydroxy in the para-position, Ris dimethylaminomethyl in the metaposition, each of R and R is hydrogen,and R is methyl.

References Cited UNITED STATES PATENTS 3,634,517 1/1972 Palopoli260--570 X ROBERT V. HINES, Primary Examiner U.S. Cl. X.R.

260-343] S, 345.7, 465 E, F, G, K, 501.11, 501.18, 501.19, 566 R;424-330, 331

